Various diseases are caused by infections by foreign bacteria. An exhaustive list of such diseases and their causative agents is not possible, but one such example is tuberculosis, caused by Mycobacterium tuberculosis. Mycobacterium intracellulare is another pathogen causing disease in humans, more so in immune compromised individuals and those with Acquired Immune Deficiency Syndrome (AIDS). Current research in the field has focused on compounds which are bactericidal and non-toxic to treat diseases caused by these organisms. Of special significance is the fact that at present no specific drugs are available to treat disease caused by M. intracellulare group of organisms.
The rifamycin family of antibiotics has received particular attention in this regard. For example, U.S. Pat. No. 4,086,344, discloses N,15-Didehydro-15-deoxo-3,15-epi (methano alkyl amino) rifamycins, in quinone or hydroquinone form. These compounds are only used in in vitro tests, however. While results which show biocidal activity in vitro can be applied for the development of, e.g., cleaning solutions, disinfectants, and so forth, in vitro efficacy is no guarantee that the subject compound will work in vivo.
U.S. Pat. No. 3,084,165 is indicative of this. This patent discloses quinone derivatives which are described as "tuberculostatic". Data are limited to in vitro situations, although the patent clearly shows that in vivo results in other areas were encouraging (e.g., suppression of aerobic glycolysis in tumor cells).
U.S. Pat. No. 4,327,096, also teaches compounds which are effective against tuberculosis in vitro. This patent teaches 3-amindino rifamycins which inhibits M. tuberculosis. This effect is also shown by U.S. Pat. No. 4,447,432, directed to azino rifamycin compounds. Additional compounds effective against tuberculosis in vitro include U.S. Pat. No. 3,691,168 (5-arylbenzo (B) (1,7) napthydrine derivatives).
In vivo success has been more limited. U.S. Pat. No. 3,995,044, discloses benzoic acid anide derivates useful against M. tuberculosis in vivo. Of particular interest according to this patent is N-(pyrid-2-yl-methyl) 3,5-dinitrobenzoic acid. This patent, filed in 1974, states that fourteen effective medicaments were known at that time. One such example, though not stated in the '044 patent, is the 2-substituted naphthiazole 4,9-quinones, and their hydroquinone and acyl derivatives, as disclosed in U.S. Pat. No. 3,039,925. This patent admits that, alone, these quinones are not as effective as standard anti-tuberculosis agents, (as an example, isonicotinic acid hydrazide is given); but, suggests combination with this semicarbazones of aromatic or heterocyclic aldehydes, streptomycin and paraaminosalicylic acid are effective.
The most recent patent teaching anti-tuberculosis compound is U.S. Pat. No. 4,499,075. This patent teaches polypeptide antibiotics derived from S. coeruleorubidus rubidus. These polypeptides are effective in vivo.
Review of this art shows that no compounds are disclosed which are effective against M. intracellulare, which is an important and difficult mycobacterial disease. Additionally, as is pointed out in U.S. Pat. No. 3,995,044, the need for additional drugs effective against M. tuberculosis continues, because of the development of resistant strains. Even with fourteen effective drugs, the '044 patent points out that combinations of three, and as many as five different drugs have been used in combination. Concerns about combinations of so many active compounds need not be repeated. The recognition, as in the '044 patent, e.g., that up to 30% of patients show side effects of anti-tuberculosis drugs, emphasizes the need for continued research in this area.
Recent research has pointed to the possible use of Vitamin K and coenzyme Q analogous as an anti-mycobacterial agent. Of particular interest is 6-cyclo-ocylamino-5,8,quinoline quinone (CQQ, or "Gangamicin" hereafter), a quinone derivative of Vitamin K, having the structure: ##STR1## and the empirical formula C.sub.17 H.sub.20 N.sub.2 O.sub.2. See, Gangadharam, et al., Am. Rev. Respir. Disease (1978). Vitamin K. as is shown in the art, is important in connection with blood clotting.
As CQQ is a quinone derivative, the possibility that it might be useful as an antitubercular drug arises. Several factors speak against it. First, as will be seen by review of the art, supra, the usefulness of one derivative is no guarantee of the usefulness of a second one. Second, as will also be realized from the art, in vitro efficacy does not guarantee, or even suggest, success in vivo. In connection with this is the not unwarranted concern over the similarity of CQQ to Vitamin K. As Vitamin K deficiency has been associated with excessive bleeding, CQQ could be expected to cause massive hemmorhaging in vivo.
Thus, while Gangadharam, et al., supra, and in Tubercle 62: 37 -41 (1981) have demonstrated that CQQ is effective against M. intracellulare and M. tuberculosis in vitro, it was not to be assumed that the compound would be efficacious in vivo. Now, however, it has been discovered that CQQ is effective against mycobacterial infection in vivo, especially against M. tuberculosis and M. intracellulare.
Hence it is an object of this invention to provide a method of in vivo treatment of mycobacterial infections, including M. tuberculosis and M. intracellulare, using the compound CQQ, also known as Gangamicin.
However these and other objects of the invention are achieved will be ascertained by review of the Detailed Description of Preferred Embodiments, which follows.